Indications: Head and Neck Cancer and Metastatic Colorectal Cancer

Head and Neck Cancer

ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN)

ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck

ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

Metastatic Colorectal Cancer

ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use:

In combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment

In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy

As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan

Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions:

Serious infusion reactions occurred with the administration of ERBITUX® (cetuximab) in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions.

Cardiopulmonary Arrest:

Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with ERBITUX and radiation therapy and in 3% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU). Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration.

EXTREME STUDY DESIGN: A LANDMARK, MULTICENTER, PHASE III TRIAL1,2

EXTREME was an open-label, randomized (1:1), multicenter, controlled clinical trial conducted outside the United States using European Union (EU)-approved cetuximab as the clinical trial material*

This trial compared EU-approved cetuximab + platinum-based therapy (cisplatin or carboplatin) with 5-fluorouracil (CT) vs CT alone; choice of cisplatin or carboplatin was at the discretion of the treating physician

ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab. These pharmacokinetic data, together with the results of the EXTREME trial and other clinical study data, establish the efficacy of ERBITUX at the recommended dose in the first-line treatment of recurrent locoregional or metastatic SCCHN

Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy

Approximately 15% of the patients in the cisplatin-alone arm switched to carboplatin during the treatment period

EXTREME STUDY: MOST COMMON ADVERSE REACTIONS1

For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU, with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU, with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death at tribute to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm

Since US-licensed ERBITUX® (cetuximab) provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

*Infusion reaction defined as any event of “anaphylactic reaction,” “hypersensitivity,” “fever and/or chills,” “dyspnea,” or “pyrexia” on the first day of dosing.

†Infection — this term excludes sepsis-related reactions which are presented separately.

THE NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®) RECOMMENDATION5

ERBITUX is indicated in combination with platinum-based therapy with 5-FU for
the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck.

5-FU=5-fluorouracil; SCCHN=squamous cell carcinoma of the head and neck.

INDICATIONS

Head and Neck Cancer

ERBITUX, in combination with radiation therapy, is approved for the initial treatment of a certain type of locally or regionally advanced head and neck cancer

ERBITUX, in combination with platinum-based chemotherapy with 5-fluorouracil, is approved for the initial treatment of patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body

ERBITUX is also approved for use alone to treat patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body and whose disease has progressed following platinum-based chemotherapy

Metastatic Colorectal Cancer

ERBITUX is approved for the treatment of certain patients who have colorectal cancer that has spread to other parts of the body. Only patients whose tumors are KRAS wild-type (which means they have a KRAS mutation-negative gene), and whose tumors have a protein called epidermal growth factor receptor (EGFR), should receive ERBITUX. FDA-approved tests are used to determine if tumors have these particular traits. Treatment with ERBITUX is given in the following three ways:

In combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for patients who are being treated for this type of cancer for the first time

In combination with another chemotherapy drug, irinotecan, for patients whose disease has progressed after receiving chemotherapy with irinotecan

As a single agent:

For patients whose disease has progressed after receiving both irinotecan and oxaliplatin

For patients who are unable to tolerate chemotherapy with irinotecan

ERBITUX is not approved to treat colorectal cancer in patients whose tumors have mutations in genes called RAS (often called "RAS mutant"), or in patients for whom the mutational status of the genes is not known.

ERBITUX is available by prescription only.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS

Allergic Reactions:

Severe allergic reactions due to ERBITUX® (cetuximab) therapy have occurred in 42 of 1373 patients (3%) receiving ERBITUX during clinical studies, resulting in death in less than 1 in 1000 patients

Symptoms can include trouble with breathing (including tightening of the airways, wheezing, or hoarseness), low blood pressure, shock, loss of consciousness, and/or heart attack. Report these signs and symptoms of infusion reactions, as well as fever, chills, or breathing problems to your doctor or nurse

Approximately 90% of the severe allergic reactions occurred with the first dose of ERBITUX, although some patients experienced their first severe allergic reaction during a subsequent dose of ERBITUX

Your doctor or nurse should watch you closely for these symptoms during treatment and may need to stop therapy in the event of an allergic reaction

Severe allergic reactions require that treatment with ERBITUX be stopped immediately and not started again

Heart Attack:

Heart attack and/or sudden death occurred in 4 of 208 patients (2%) with head and neck cancer treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone

Heart problems resulting in death and/or sudden death occurred in 7 of 219 patients (3%) with head and neck cancer treated with platinum-based chemotherapy with 5-fluorouracil and cetuximab compared to 4 of 215 patients (2%) treated with chemotherapy alone, based on a study conducted in Europe using European cetuximab

Notify your doctor if you have a history of any heart disease

Lung Disease

Lung disease, which resulted in one death, occurred in 4 of 1570 patients (<0.5%) receiving ERBITUX in several clinical trials in colorectal cancer and head and neck cancer

Notify your doctor if you develop shortness of breath while receiving ERBITUX

ERBITUX treatment should be stopped if symptoms worsen or lung disease is confirmed

Skin Problems

In several clinical trials in colorectal cancer and head and neck cancer with ERBITUX, skin problems including an acne-like rash, skin drying and cracking, infections (including infections of the blood, skin, eyes, and lips), and abnormal hair growth were seen

Sun exposure may worsen these effects

Patients taking ERBITUX should wear sunscreen and hats to limit sun exposure while receiving and for 2 months following the last dose of ERBITUX

Severe reactions with symptoms of rash; blistering of the skin, mouth, eyes, and genitals; and shedding of the skin have been seen in patients treated with ERBITUX. These reactions may be life-threatening and possibly lead to death. It is not clear if these reactions are related to the way ERBITUX works or to an immune response, such as Stevens-Johnson syndrome or toxic epidermal necrolysis

A related nail disorder that causes painful swelling of the skin around the nails—most often of the large toes and thumbs—also was reported

Notify your doctor if you develop any of these symptoms while receiving ERBITUX

ERBITUX Plus Chemotherapy and Radiation

In a controlled study, 940 patients with head and neck cancer received either ERBITUX with radiation therapy and cisplatin (a cancer drug) or radiation therapy and cisplatin alone. Adding ERBITUX resulted in an increase in occurrence of severe or life-threatening redness and sores of the lining of the mouth, lips or throat and other digestive organs; skin reactions caused by certain cancer drugs given after radiation; acne-like rash; heart problems and blood electrolyte disturbances compared to radiation and cisplatin alone

Side effects resulting in death occurred in 20 patients (4.4%) in the ERBITUX treatment arm, and 14 patients (3.0%) in the radiation therapy and cisplatin alone treatment arm

The percentage of severe late radiation side effects was similar among patients given radiation therapy alone and patients given ERBITUX plus radiation therapy

Pregnancy and Nursing

Notify your doctor if you are pregnant or if you become pregnant while receiving ERBITUX. Contraception must be used, in both males and females, during ERBITUX therapy and for 6 months following the last dose of ERBITUX. ERBITUX may be passed from the mother to the developing fetus, and may cause harm to the fetus. ERBITUX should only be used during pregnancy if the potential benefit is greater than the potential risk to the fetus

ERBITUX may be passed through human breast milk. Because of the potential for serious side effects in nursing infants from ERBITUX, nursing is not recommended during ERBITUX therapy and for 2 months following the last dose of ERBITUX

Serious side effects reported by at least 10% of patients in either arm were: infection (11% versus 8%)

ERBITUX yields approximately 22% higher blood levels of cetuximab relative to European cetuximab. It is possible that U.S. patients receiving ERBITUX may experience more frequent or severe side effects than patients in the study conducted in Europe

In a study of European cetuximab in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) given to 317 patients versus FOLFIRI alone given to 350 patients with colorectal cancer that had spread to other parts of the body whose tumors were KRAS wild-type and whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR):

ERBITUX yields approximately 22% higher blood levels of cetuximab relative to European cetuximab. In this study, the side effects and severity of adverse reactions seen with European cetuximab were consistent with other studies of U.S. patients receiving ERBITUX for metastatic colorectal cancer

In a study where ERBITUX and supportive care were given to 118 patients versus supportive care which was given to 124 patients with colorectal cancer that had spread to other parts of the body whose tumors were KRAS wild-type and whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR):

In studies where ERBITUX and irinotecan were given to 354 patients with colorectal cancer that had spread to other parts of the body whose tumors had a protein called Epidermal Growth Factor Receptor (EGFR):

You are encouraged to report negative side effects of Prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see full Prescribing Information for ERBITUX, including Boxed Warnings for allergic reactions and heart attack.

CE CON ISI_ALL 17JUN2015

INDICATIONS

Head and Neck Cancer

ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN)

ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck

ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

Metastatic Colorectal Cancer

ERBITUX is indicated for the treatment of KRAS wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use:

In combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment

In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy

As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan

Limitation of Use: ERBITUX is not indicated for treatment of RAS-mutant colorectal cancer or when the results of the RAS mutation tests are unknown.

Important Safety Information including Boxed Warnings

Infusion Reactions:

Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000

Approximately 90% of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines

Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions

Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest:

Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (5-FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin

Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks

Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity

Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD

Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients. Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days

Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with ERBITUX. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis)

ERBITUX Plus Radiation Therapy and Cisplatin

In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either ERBITUX in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of ERBITUX resulted in an increase in the incidence of Grade 3-4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone

Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the ERBITUX combination arm and 14 patients (3.0%) in the control arm

Nine patients in the ERBITUX arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm

The addition of ERBITUX to radiation and cisplatin did not improve progression-free survival (the primary endpoint)

Electrolyte Depletion

Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2, the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3-4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3-4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy

Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy

ERBITUX is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS

Based on retrospective subset analyses of RAS-mutant and wild-type populations across several randomized clinical trials of anti-EGFR-directed monoclonal antibodies, including Study 4, use of cetuximab in patients with RAS mutations resulted in no clinical benefit with treatment related toxicity

The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing

In women of childbearing potential and men, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus

It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

The most frequent adverse reactions seen in patients with KRAS wild-type, EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

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